Biphenyl compounds and use thereof as oestrogenic agents

ABSTRACT

Compounds of formula (I), wherein [X] represents aromatic carbocyclic rings (A) and (B), where R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are as defined in the description, salts thereof, a method and intermediates for preparing same, the use thereof as drugs, and pharmaceutical compositions containing same, are disclosed. ##STR1##

This application is a 371 of PCT/FR97/00184 filed Jan. 30, 1997.

A subject of the invention is new biphenyl compounds, their preparationprocess and the intermediates of this process, their use as medicamentsand the pharmaceutical compositions containing them.

A subject of the invention is the compounds of general formula (I):##STR2## in which [X] represent the following aromatic carbocycles:##STR3## in which R₁ represents an alkyl radical containing from 1 to 4carbon atoms or a hydrogen atom, R₂ represents an alkyl radicalcontaining from 1 to 4 carbon atoms or a hydrogen atom, R₃ represents ahydrogen atom, a halogen atom, an alkyl radical containing from 1 to 4carbon atoms or an alkoxy radical containing from 1 to 4 carbon atoms,R₄ in para or meta position represents a hydrogen atom, a halogen atom,a hydroxyl radical, an alkyl, alkenyl or alkynyl radical containing atmost 4 carbon atoms, an alkoxy, alkylthio radical in which alkylcontains from 1 to 4 carbon atoms, an --NR_(A) R_(B) group in whichR_(A) and R_(B) identical or different represent a hydrogen atom, analkyl radical containing from 1 to 4 carbon atoms or form together withthe nitrogen to which they are linked a saturated heterocycle with 5 or6 members optionally containing a second heteroatom chosen fromnitrogen, oxygen and sulphur, their --NR_(A) R_(B) group beingoptionally in oxidized form, a group of general formula --O--(CH₂)_(n)--NR_(A) R_(B) in which n is an integer which varies from 2 to 7 and inwhich --NR_(A) R_(B) is as defined previously, R₅ represents a hydrogenatom or a halogen atom, R₆ and R₇ identical or different represent ahydrogen atom, a halogen atom, an alkyl radical containing from 1 to 4carbon atoms, or a phenyl radical optionally substituted in meta or paraposition by an R₄ radical as defined previously as well as the additionsalts with acids or bases, with the exception of the compounds offormula (I) in which [X] represents the group (A) in which R₁, R₂, R₃are hydrogen atoms and R₄ represents a hydroxyl radical and those inwhich [X] represents the group (B) in which R₅, R₆ and R₇ are hydrogenatoms or R₅ and R₆ are hydrogen atoms and R₇ represents an alkyl radicalcontaining from 1 to 4 carbon atoms.

When R₁, R₂, R₃, R₄, R₆, R₇, R_(A) and R_(B) represent an alkyl radicalcontaining from 1 to 4 carbon atoms, it is a methyl, ethyl, propyl,isopropyl, butyl, isobutyl or tert-butyl radical. When R₃, R₄, R₅, R₆and R₇ are halogen atoms, it is fluorine, chlorine, bromine or iodine.Preferably, it is chlorine. When R₄ is an alkenyl radical containing atmost 4 carbon atoms, preferably it is a vinyl or propenyl radical. WhenR₄ is an alkynyl radical containing at most 4 carbon atoms, preferablyit is an ethynyl or propynyl radical. When R₃ or R₄ represent analkyloxy radical containing from 1 to 4 carbon atoms, preferably it is amethoxy, ethoxy, propyloxy, isopropyloxy or butyloxy radical. When R₄ isan alkylthio radical containing from 1 to 4 carbon atoms, preferably itis a methylthio, ethylthio, propylthio, isopropylthio or butylthioradical. When R₄ is an NR_(A) R_(B) radical in which R_(A) and R_(B)identical or different represent a hydrogen atom or an alkyl radicalcontaining from 1 to 4 carbon atoms, preferably it is an amino,methylamino, ethylamino, dimethylamino, diethylamino or methylethylaminoradical. When R₄ is an --NR_(A) R_(B) group in which R_(A) and R_(B)form with the nitrogen a saturated heterocycle, preferably it ispyrrolidino, piperidino, piperazino, morpholino or thiomorpholinogroups, each of these amino groups being optionally in oxidized form.

Naturally the invention extends to the salts of the compounds de formula(I), in particular when the compounds of formula (I) contain an aminofunction. These are the salts formed for example with the followingacids: hydrochloric, hydrobromic, nitric, sulphuric, phosphoric, acetic,formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric,oxalic, glyoxylic, aspartic, alkanesulphonics such as methane- andethanesulphonics, arenesulphonics, such as benzene and paratoluenesulphonics and arylcarboxylics.

These are also the salts formed under the action of a base or an alkalior alkaline-earth metal, in order to obtain for example derivatives suchas sodium or potassium alcoholate or derivatives such as potassium orsodium phenolate.

A more particular subject of the invention is the compounds of generalformula (I) as defined previously in which [X] is the aromaticcarbocycle of general formula (A).

A more particular subject of the invention is the products of generalformula (I) as defined previously in which [X] is the aromaticcarbocycle of general formula (B).

A more particular subject of the invention is the products of generalformula (I) as defined above, corresponding to general formula (I'):##STR4## in which R'₁, R'₂ and R'₃ represent a hydrogen atom or an alkylradical containing from 1 to 4 carbon atoms, R'₄ in meta or paraposition represents a hydrogen atom, a halogen atom, a hydroxyl radical,an alkyl radical, an --NR_(A) R_(B) group or an --O--(CH₂)_(n) --NR_(A)R_(B) group, n, R_(A) and R_(B) being as defined previously, as well asthe addition salts with acids. When R'₄ is an --O--(CH₂)_(n) --NR_(A)R_(B) group, it is preferably the --O--(CH₂)₂ --NMe₂ group.

A more particular subject of the invention is the products of generalformula (I) as defined previously corresponding to general formula (I')in which R'₁, R'₂ and R'₃ are hydrogen atoms.

A quite particular subject of the invention is the compound of generalformula (I) as defined previously in which R₆ represents a halogen atomor an --O--(CH₂)₂ --N(CH₃)₂ group and R₇ represents a hydrogen atom.

A quite particular subject of the invention is the compound of generalformula (I) as defined above the names of which follow:

5-[4-[2-(dimethylamino) ethoxy] phenyl] 6-(4-hydroxyphenyl)2-naphthalenol,

1,5-dichloro-6-(4-hydroxyphenyl)-2-naphthalenol,

5-chloro-6-(4-hydroxyphenyl)-2-naphthalenol.

A subject of the invention is also a preparation process for theproducts of formula (I) as defined above characterized in that a productof formula (II):

    G--[X]--OP'                                                (II)

in which [X] is as defined previously, P' represents a protective group,and G represents a halogen atom or an OSO₂ CF₃ group is subjected to theaction, in the presence of a catalyst, of a product of formula (III):##STR5## in which Y represents a halogen atom, a B(OH)₂ group or anSn(R)₃ group, in which R represents an alkyl group containing from 1 to8 carbon atoms and P represents a protective group identical to ordifferent from P', in order to obtain a product of formula (IV):##STR6## in which P, P' and [X] have the same meaning as previously,which product of formula (IV) is subjected to one or more deprotectionreactions in order to obtain the product of formula (I) as definedpreviously which, if appropriate is subjected to the action of an acidor base in order to obtain the corresponding salt.

The formation of the biphenyls of formula (IV) by coupling the aromaticcompound of formula (II) with the aromatic compound of formula (III) iscarried out in the presence of a catalyst chosen from the derivatives ofpalladium or in the presence of copper in the case where Y is an iodineatom and can therefore be carried out under the conditions described inthe following articles:

A. Huth, I. Beetz and I. Schumann Tetrahedron (1989) 45 6679:Conditions: Na₂ CO₃ 2M/Pd(PΦ₃)₄ /Toluene/LiCl/EtOH/Δ)

J. K. Stille Ang. Chem. Int. Ed. (1986) 25 508: Conditions: Pd(PΦ₃)₄/LiCl/Dioxane/Δ)

T. Oh-e, N. Migawa and A. Suzuki J. Org. Chem. (1993) 58 2201-2208:Conditions: K₃ PO₄ /KBr/Pd(PΦ₃)₄ /Dioxane/Δ)

P. E. Fank Chem. Rev. (1964) 38 139: Conditions: Cu/DMF/120° C. in thecase where Y is an iodine atom.

E. Erdik Tetrahedron (1992) 48 9577: Conditions: nBuLi/THF/-78° C.-2)ZnCl2-3) ArBr/Pd(PΦ₃)₄ /)Δ4)HCl/MeOH.

A subject of the invention is also a preparation process for products offormula (I) in which [X] is the aromatic carbocycle of formula (A) asdefined above characterized in that a product de formula (V): ##STR7##in which R₄ and P are as defined previously, is subjected to the actionof the methylvinylketone of general formula (VI): ##STR8## in which R₁,R₂ and R₃ are as defined previously, in order to obtain the product offormula (VII): ##STR9## in which R₁, R₂, R₃, R₄ and P are as definedpreviously, which is subjected to the action of a dehydration andaromatization reagent in order to obtain the product of formula (VIII):##STR10## in which R₁, R₂, R₃, R₄ and P are as defined previously, whichis subjected to the action of a deprotection reagent in order to obtainthe products of formula (I) in which [X] is the aromatic carbocycle offormula (A) which, if desired, is subjected to the action of an acid inorder to obtain a corresponding salt.

The protective groups P or P' are preferably chosen from an alkylradical containing from 1 to 4 carbon atoms, a benzyl group and an R_(C)R_(D) R_(E) Si group, in which R_(C), R_(D) and R_(E) identical ordifferent represent an alkyl radical containing from 1 to 4 carbon atomsor a phenyl group. It will be quite particularly methyl, phenyl,terbutyldimethylsilyl and terbutyldiphenylsilyl radicals.

The action of the methylvinylketone of general formula (III) on theproduct of formula (II) is preferably carried out in the presence of abase such as potash in a dioxane/water mixture.

The dehydration and aromatization reaction is carried out for exampleusing a mineral acid such as phosphoric acid at a temperature of 150° C.for 4 hours.

The deprotection reactions are the standard deprotection methods knownto a person skilled in the art. A fairly complete list is found in thefollowing work: Protective groups in organic synthesis T. W greene, JohnWiley & sons (1981).

By way of example, when P or P' represent a methyl radical thedeprotection reaction can be carried out by the action of tribromoboranein dichloromethane or hydrochloric acid in pyridine. When P or P'represents a benzyl group a catalytic hydrogenation or a hydrolysis canbe carried out with trifluoroacetic acid. When P or P' represents asilyl group the deprotection can be carried out with tetra-butylammoniumfluoride (TBAF) in tetrahydrofuran (THF).

Salification by an acid or a base is carried out under standardconditions. The operation is carried out for example with hydrochloricacid, in an ethereal solution.

The compounds of formula (I) as well as their addition salts withpharmaceutically acceptable acids or bases are particularly usefulproducts from a pharmacological point of view.

They are the original ligands of the oestrogen receptor. As such, theycan be used in the treatment of disorders linked to hypofolliculinia,for example, amenorrheas, dysmenorrheas, repeated abortions,premenstrual disorders, in the treatment of certain oestrogen-dependentpathologies such as prostatic adenomas or carcinomas, mammary carcinomasand their metastases or in the treatment of benign tumors of the breast,both as an antiuterotrophic as well as in replacement treatment ofsymptoms linked to the menopause and in particular osteoporosis.

Therefore, a subject of the invention is, as medicaments, the productsof formula (I) as described previously as well as their addition saltswith pharmaceutically acceptable acids or bases.

A more particular subject of the invention is, as medicaments, thecompounds of formula (I) as described previously corresponding togeneral formula (I') as described previously as well as the additionsalts with pharmaceutically acceptable acids or bases.

A quite particular subject of the invention is, as medicaments, thefollowing products of formula (I):

5-[4-[2-(dimethylamino) ethoxy] phenyl) 6-(4-hydroxy-phenyl)

2-naphthalenol,

5-chloro-6-(4-hydroxyphenyl)2-naphthalenol,

1,5-dichloro-6-(4-hydroxyphenyl)-2-naphthalenol.

The invention extends to the pharmaceutical compositions containing atleast one medicament as defined above as active ingredient.

The compositions of formula (I) are used by digestive, parenteral orlocal route, for example by percutaneous route. They can be prescribedin the form of plain or sugar-coated tablets, capsules, granules,suppositories, pessaries, injectable preparations, ointments, creams,gels, microspheres, implants, patches which are prepared according tothe usual methods.

The active ingredient or ingredients can be incorporated with excipientsusually employed in these pharmaceutical compositions, such as talc, gumarabic, lactose, starch, magnesium stearate, cocoa butter, aqueous ornon-aqueous vehicles, fatty substances of animal or vegetable origin,paraffin derivatives, glycols, various wetting, dispersing oremulsifying agents, preservatives.

The dose varies according to the illness treated and the administrationroute: it can be, for example, from 1 mg to 100 mg per day by oralroute, for an adult.

The products of general formula (V) as defined above are obtained by theaction of the product of general formula (IX): ##STR11## with a productof general formula (X): ##STR12## in the presence of a strong base suchas LDA (lithium diisopropylamide). This reaction is described in: S.HUNIG et al. Chem. Ber. (1980) 113, 324-332

The products of formula (X) are obtained by the action of trimethylsilyl cyanide in the presence of a Lewis acid such as ZnI₂, on thecorresponding aldehyde of general formula (XI): ##STR13## This reactionis described in Synthesis (1980) p. 861-868. The protected products offormula (IX) are obtained from parahydroxy benzaldehyde by standardprotection methods for alcohols described in the work by T. W. Greenementioned above.

The products of formulae (II), (III), (IX), (X) and (XI) are commercialproducts or are easily accessible by standard functionalization methodsfor aromatic compounds known to a person skilled in the art.

The products of formula (VI) are also easily accessible to a personskilled in the art.

The products of formula (V) in which R₄ is an alkyloxy containing from 1to 4 carbon atoms in para position and P is an alkyl containing from 1to 4 carbon atoms, are known and are described in the followingreferences: Chemical Abstract: 65-10442b, 112-148858n, 59-9865f.

Finally, a subject of the invention is, as new industrial products andin particular as new intermediate products necessary for theimplementation of the invention, the products of general formulae (IV),(V), (VII) and (VIII) as defined previously, with the exception of theproducts of formula (V) in which R₄ is an alkyloxy containing from 1 to4 carbon atoms or a halogen atom and P is an alkyl radical containingfrom 1 to 4 carbon atoms and with the exception of the products deformulae (VII) and (VIII) in which R₄ is a methoxy radical, P is amethyl radical and R₁, R₂ and R₃ are hydrogen atoms, and with theexception of the products of formula (IV) in which P and P' are methylor acyl radicals, X represents the group B in which R₅, R₆ and R₇ arehydrogen atoms.

The following examples illustrate the invention without however limitingit:

PREPARATION 1 [4-(phenylmethoxy)phenyl]-boronic acid

Stage A: 1-bromo-4-(phenylmethoxy)-benzene

15.26 g of sodium hydride at 50% in oil is added at 0° C. to a solutionunder inert gas of 50 g of parabromophenol in 320 ml ofdimethylformamide (DMF), agitation is carried out for 30 minutes at 0°C., then 37.7 ml of benzyl bromide is added. Agitation is carried outfor 2 hours 30 minutes while allowing the temperature to rise to 20° C.,then the reaction mixture is poured into ice-cooled water, theprecipitate is filtered, and dried. 73.35 g of expected product isobtained. Rf: 0.85 (thin layer chromatography, support: silica, eluant:cyclohexane/ethyl acetate 7/3).

I.R. spectrum: (CHCl₃) Absence of OH Aromatic 1592, 1580 and 1488 cm⁻¹.

Stage B: [4-(phenylmethoxy)phenyl]-boronic acid

143 ml of a solution of n-Butyllithium (nBuLi) is added dropwise, underinert gas and at -78° C., to 47.08 g of the product obtained in Stage Ain 375 ml of tetrahydrofuran (THF), agitation is carried out for 1 hour,then 36.5 ml of triethylborate is added. Agitation is carried out for 14hours, while leaving the temperature to rise to 20° C., and the reactionmedium is hydrolyzed using a solution of ice-cooled water containing 45ml of concentrated sulphuric acid, for 1 hour at 20° C. The aqueousphase is extracted with ethyl acetate, the organic phases are washedwith 2N soda and the aqueous phase is acidified to pH=1 using a 1Nsolution of hydrochloric acid in order to precipitate the boronic acid.After filtration and drying the precipitate 28.54 g of expected productis obtained. Rf: 0.16 cyclohexane/ethyl acetate 7/3) I.R. spectrum:(Nujol)

    ______________________________________                                        General absorption                                                                            3650, 3615, 3510 and 3420 cm.sup.-1                           OH/NH region                                                                  Aromatic        1605, 1570 and 1510 cm.sup.-1                                 B--O            1410, 1340 cm.sup.-1                                          ______________________________________                                    

PREPARATION 2 [4-[[(1,1-dimethylethyl)diphenylsilyl] oxy]phenyl]-boronicacid

Stage A: 1-Bromo-4-[[(1,1-dimethylethyl)diphenylsilyl]oxy] benzene

400 ml of dimethylformamide, 31.18 g of imidazole and 125.89 g of1,1-dimethyl-ethyl-diphenyl-chlorosilane are added under an inertatmosphere and at ambient temperature to 80.89 g of parabromophenol,then the solution obtained is agitated for 2 hours. The reaction mediumis poured into 2 litres of water, precipitation is observed, the solidis solubilized with ethyl acetate and the aqueous phase is extractedwith ethyl acetate, the combined organic phases are dried and evaporatedunder reduced pressure until an oil is obtained. Pentane is added andcrystallization is observed. After filtration and drying the precipitate179.24 g of expected product is obtained. Rf: 0.53 (thin layerchromatography, support: silica, eluant Cyclohexane/AcOEt 95/5). Meltingpoint: 56° C. NMR (CDCl₃, 300 MHz)

    ______________________________________                                               1.09 s       SitBu                                                            6.63 m       H.sub.3, H.sub.5                                                 7.17 m       H.sub.2, H.sub.6                                                 7.69 dd      4H for SiΦ2                                                  7.4          6H for SiΦ2                                           ______________________________________                                    

Stage B: [4-[[(1,1-dimethylethyl)diphenylsilyl]oxy] phenyl]-boronic acid

60 ml of a solution of n-butyl-lithium is added dropwise at -78° C. andunder inert gas to a solution of 30 g of the product of the precedingstage in 100 ml of anhydrous tetrahydrofuran, then after agitation for30 minutes at -78° C., 9.95 ml of trimethylborate is added. Afteragitation for 2 hours 30 minutes, the bath temperature having risen to11.9° C., 20 ml of water is added dropwise and agitation is carried outfor 72 hours at ambient temperature. After evaporation of thetetrahydrofuran under reduced pressure, the aqueous phase is 5 extractedwith ether, followed by drying and concentrating under reduced pressureuntil an oil is obtained (26.35 g) which is purified by filtrationchromatography on silica with a hexane/ethyl acetate mixture 1/1 inorder to obtain 7.73 g of expected product in the form of the dimer.

IR (CHCl₃)

    ______________________________________                                        O--Si              915 and 1255 cm.sup.-1                                     B--O               1350 and 1370 cm.sup.-1                                    Aromatics          1515, 1570 and 1602 cm.sup.-1                              NMR (CDCl.sub.3)                                                              1.11               tBu                                                        6.81 and 7.88      Ph--O                                                      7.3 and 7.5 (6H) and 7.72 (4H)                                                                   PhSi                                                       ______________________________________                                    

PREPARATION 3 (4-methoxyphenyl)-boronic acid

100 ml of a solution of 10 g of p-bromoanisole in anhydrous diethylether is added dropwise under reflux to a suspension, under inert gas,of 1.3 g of magnesium turnings in 5 ml of anhydrous diethyl ether, andthe mixture is left under reflux for 2 hours. The reaction medium isthen poured into a solution of 9.02 ml of triethylborate in 60 ml ofanhydrous ether cooled down to -70° C. After agitation for 1 hour at-70° C., then for 1 hour at ambient temperature, the solution is pouredinto a mixture containing 11 ml of sulphuric acid and 50 g of ice andwater and agitation is carried out for 1 hour. The organic phase isextracted with 100 ml of a saturated aqueous solution of sodiumbicarbonate, the aqueous phases are combined, reacidified with 6Nhydrochloric acid, extracted with ether, dried and evaporated underreduced pressure. 3.9 g of expected product is obtained.

I.R. spectrum: (Nujol) Complex absorption OH/NH region, 1609, 1573 and1518 cm⁻¹.

NMR (DMSO-d6, 300 MHz)

    ______________________________________                                        3.76 s                OCH.sub.3                                               6.88 d J = 9Hz        H.sub.3 and H.sub.5                                     7.78 d J = 9Hz        H.sub.2 and H.sub.6                                     7.86                  B(OH).sub.2                                             ______________________________________                                    

PREPARATION 4 4-(dimethylaminoethoxy) phenyl boronate.

2.5 g of 1-bromo 4-(dimethylamino) ethoxy benzene described in thePatent RO 83118 in 50 ml of tetrahydrofuran is cooled down to -78° C.then 7.86 ml of n-butyllithium is added over 5 minutes. Agitation iscarried out for 30 minutes at -78° C., 1.35 ml of trimethyl borate isadded over 10 minutes, the reaction medium is maintained for 2 hoursunder agitation at -78 ° C. then for 3 hours at ambient temperature. 3ml of water is added dropwise and agitation is carried out for 72 hoursat ambient temperature. The solvent is evaporated off under reducedpressure, the residue is chromatographed on silica (eluant THF) then onneutral alumina (eluant: CH₂ Cl₂ then CH₂ Cl₂ -MeOH 95-5). 810 mg ofexpected product is obtained. Rf=0.2 (CH₂ Cl₂ --MeOH 95-5).

EXAMPLE 1 5-[-4-[2-(dimethylamino) ethoxy] phenyl] 6-(4-hydroxyphenyl)2-naphthalenol.

Stage A: 1-[4-[2-(dimethylamino) ethoxy] phenyl] 6-methoxy2-naphthalenol.

a) 1-bromo 6-methoxy 2-naphthalenol.

1.05 g of 6-methoxy 2-naphthalenol prepared as in Example 2 Stage A in15 ml of ethanol, 0.84 g of N-bromoacetamide is added and agitation iscarried out for 1 hour at ambient temperature. The reaction medium ispoured into 800 ml of water followed by extraction with methylenechloride, drying, the solvent is evaporated off under reduced pressure,the residue is purified by chromatography on silica (eluant:cyclohexane-dichloromethane 50-50). 0.75 g of expected product iscollected.

b) 2.5 g of the product obtained as in Stage a) with 2,45 g of4-(dimethylaminoethoxy) phenyl boronate prepared as indicated inPreparation 4 in 150 ml of dioxane is agitated under reflux for 3 hoursin the presence of 0.85 g of palladium tetrakis and 3.8 g of potassiumphosphate mono-hydrate. The solvent is evaporated off under reducedpressure, the residue is chromatographed on silica (eluant:dichloromethane-methanol 95-5) and 1.8 g of expected product isobtained.

Stage B: 1-[4-(2-dimethylamino) ethoxy] phenyl] 6-methoxy 2-naphthalenoltrifluoromethanesulphonate.

1 g of the product obtained in Stage A is mixed with 30 ml of pyridinethen 1.25 ml triflic anhydride is added. The reaction medium is heatedfor 3 hours at 80°-90° C., then poured into a saturated aqueous solutionof sodium bicarbonate. Extraction is carried out with ethyl acetate,followed by drying, the solvent is evaporated off under reducedpressure, the residue is chromatographed on silica (eluant:cyclohexane-ethyl acetate 7-3 then dichloromethane-methanol 95-5). 0.72g of expected product is obtained. Rf=0.3 (eluant: CH₂ Cl₂ --CH₃ OH95-5).

Stage C: N,N-dimethyl 2-[4-[6-methoxy 2-(4-methoxyphenyl)1-naphthalenyl] phenoxy] ethanamine.

0.64 g of the triflate obtained in Stage B with 274 mg of4-methoxyphenyl boronic acid prepared as indicated in Preparation 3 in30 ml of dimethylformamide is heated for 3 hours at 120° C. in thepresence of 32 mg of dipalladium tris(dibenzylideneacetone), 505 mg ofpotassium phosphate monohydrate, 177 mg of potassium bromide and 73 mgof triphenylphosphine. The solvent is evaporated off under reducedpressure, the residue is chromatographed on silica (eluant:dichloromethane-methanol 95-5 then ethyl acetate-acetone-methanol80-10-10). 0.28 g of expected product is obtained. Rf=0.16(AcOEt--(CH₃)₂ CO--CH₃ OH 80-10-10).

IR spectrum (CHCl₃) aromatic: 1625, 1610, 1600, 1572, 1515, 1499 cm⁻¹

Stage D: 5-[-4-[2-(dimethylamino) ethoxy] phenyl] 6-(4-hydroxyphenyl)2-naphthalenol.

95 mg of the product obtained as in Stage C is heated for 1 hour at 200°C. with 1.2 g of pyridinium hydrochloride, followed by taking up in asaturated aqueous solution of sodium bicarbonate, extraction with ethylacetate and drying, the solvent is evaporated off under reducedpressure, the residue is chromatographed on silica (eluant:dichloromethane-methanol 90-10) and 35 mg of expected product isobtained. Rf=0.07 (AcOEt--(CH₃)₂ --CO--CH₃ OH 80-10-10).

IR spectrum (Nujol); aromatic: 1620, 1608, 1508 cm⁻¹.

EXAMPLE 2 5-chloro-6-(4-hydroxyphenyl)-2-naphthalenol

Stage A: protection of the naphthol 2-hydroxy-6-methoxy-naphthalene

3.75 ml of methyl sulphate and 0.8 g of soda are added, under an inertatmosphere to 3.2 g of 2,6-dihydroxy-naphthalene in 20 ml of methanoland 3 ml of water, and the reaction medium is heated for 15 hours at 40°C. After having poured the reaction medium into 200 ml of water,extraction is carried out with ethyl acetate, followed by drying,filtering and evaporating under reduced pressure. The crude product ispurified by chromatography and 1.2 g of expected product is obtained aswell as 1.6 g of biprotected analogue. Rf=0.24 (cyclohexane/ethylacetate 80/20) NMR (CDCl₃)

    ______________________________________                                        3.90 (s)             OCH.sub.3                                                4.89 (ws)            OH                                                       7.58 d; 7.64 d       H.sub.4 ; H.sub.8                                        7.03 to 7.15 m 4H    H.sub.1, H.sub.3, H.sub.5, H.sub.7                       ______________________________________                                    

Stage B: Chlorination 1-chloro-2-hydroxy-6-methoxy-naphthalene

175 mg of the product prepared in the preceding stage is added under aninert atmosphere to a solution of thionyl chloride in 5 ml of chloroformat ambient temperature and agitation is carried out for 1 hour. Afterwashing with water, drying, filtration and evaporation under reducedpressure, 200 mg of expected product is obtained. Rf=0.25(cyclohexane/ethyl acetate 70/30) NMR (CDCl₃)

    ______________________________________                                        3.91 s                 OCH.sub.3                                              5.71 s                 OH                                                     7.59 d; 7.97 d         H.sub.4 ; H.sub.8                                      7.23 m                 H.sub.3                                                7.11 d J = 2,5Hz       H.sub.5                                                7.23 m                 H.sub.7                                                ______________________________________                                    

Stage C: formation of the triflate1-chloro-2-trifluoromethylsulphonyloxy-6-methoxy-naphthalene

0.75 ml of triflic anhydride is added at 0° C. to a solution, under aninert atmosphere of 600 mg of the chloronaphthol obtained in thepreceding stage in 50 ml of pyridine, and agitation is carried out for1.5 hours at ambient temperature. The reaction medium is then pouredinto 300 ml of water, followed by extraction with ethyl acetate, drying,filtering then evaporation under reduced pressure. 1 g of expectedproduct is obtained which used as it is in the following stage. Rf=0.28(cyclohexane/ethyl acetate 70/30)

Stage D: Coupling1-chloro-2-(4-[[(1,1-dimethylethyl)diphenylsilyl]oxy]phenyl)-6-methoxy-naphthalene

A mixture constituted by 1 g of the triflate prepared in the precedingstage, 1.5 g of the boronic acid obtained in Preparation 2, 420 mg ofpotassium bromide, 1.1 g of potassium phosphate monohydrate, 100 mg ofpalladium tetrakis and 50 ml of dioxane are mixed together for 8 hours,under an inert atmosphere, under reflux. After washing with water,drying, filtration then evaporation under reduced pressure, the crudeproduct is purified by chromatography eluting with a cyclohexane/ethylacetate mixture 97/3. 1.4 g of expected product is obtained. Rf=0.55(cyclohexane/ethyl acetate 90/10)

Stage E: Deprotection (desilylation)1-chloro-2-(4-hydroxyphenyl)-6-methoxy-naphthalene

700 mg of the product obtained in the preceding stage in 50 ml oftetrahydrofuran and 1.5 ml of tetrabutylammonium fluoride (1M/THF) areagitated for 30 minutes, under an inert atmosphere and at ambienttemperature. After evaporation under reduced pressure, the crude productis purified by chromatography eluting with a cyclohexane/ethyl acetatemixture 90/10. 300 mg of expected product is obtained. Rf=0.45(cyclohexane/ethyl acetate 70/30) NMR (CDCl₃)

    ______________________________________                                        3.95 s               OCH.sub.3                                                4.84 ml              OH                                                       7.16 d               H.sub.5                                                  7.29 dd              H.sub.7                                                  7.40 d, 7.68 dd, 8.29 d                                                                            H.sub.3, H.sub.4, H.sub.8                                6.93; 7.40           H of Ph--OH                                              ______________________________________                                    

Stage F: Deprotection: demethylation5-chloro-6-(4-hydroxyphenyl)-2-naphthalenol

300 mg of the product obtained in the preceding stage and 3 g ofpyridinium hydrochloride are mixed together under an inert atmosphereand the reaction medium is heated for 2 hours at 200° C. After havingpoured the reaction medium into 30 ml of water, extraction is carriedout with ethyl acetate, followed by washing with water, drying,filtering and evaporation under reduced pressure. The crude product ispurified by chromatography eluting with a dichloromethane/ether mixture95/5. 120 mg of pure expected product is obtained. Rf=0.20(cyclohexane/ethyl acetate 70/30) M.p.=254° C.

NMR (CDCl₃)

    ______________________________________                                        7.20 to 7.40 m,  H of naphthyl                                                7.71 dl, 8.13 dl                                                              6.87; 7.30       H of Ph--OH                                                  9.57 s; 10.00 s  OH (Ph--OH, Naphth-OH)                                       ______________________________________                                    

EXAMPLE 3 1,5-dichloro-6-(4-hydroxyphenyl)-2-naphthalenol

The operation is carried out in a similar manner to Example 2 startingwith 100 mg of 1,5-dichloro-2-hydroxy-6-methoxy-naphthalene (obtained bythe action of 0.35 ml of sulphuryl chloride on 350 mg of the product ofExample 2 Stage A in 20 ml of dichloromethane with a yield of 100%) andby using the boronic acid of Preparation 1, 15 mg of pure expectedproduct is obtained.

Rf=0.60 (cyclohexane/ethyl acetate 50/50) NMR (CDCl₃)

    ______________________________________                                        7.40; 7.53 d; 8.04 d; 8.30 d                                                                     H of naphthyl                                              6.94; 7.430        H of Ph--OH                                                4.85 wm; 5.92 wm   (Ph--OH, Naphth-OH)                                        ______________________________________                                    

Pharmaceutical Composition

Tablets were prepared corresponding to the following general formula:

product of Example 2 50 mg

Excipient (talc, starch, magnesium stearate) qs for a tablet completedat 120 mg

Pharmacological Study of the Products of the Invention

Human Oestrogen Receptor (HOR)

A cytosolic extract of SF9 cells containing the recombinant humanoestrogen receptor is obtained by overexpression in aninsect-Baculovirus cell system, according to the general methodologydescribed by N.R. WEBB et al. (Journal of Methods in Cell and MolecularBiology, (1990) Vol.2 No. 4, 173-188) and the application of which isdescribed for the expression of human hormonal receptors, for examplethe human glucocorticoid receptor (G. SRINIVASAN et al. MolecularEndocrinology (1990) vol 4 No. 2 209-216).

The BaculoGold Transfection Kit (PharMingen, reference 21000K) is usedto generate the recombinant baculovirus containing the cDNA fragmentdescribed in the expression vector HEGO by L. TORA et al. (The EMBOJournal (1989) vol. 8 No. 7 1981-1986), containing the region coding forthe wild-type human oestrogen receptor with a glycine in position 400.

The recombinant virus thus obtained is used to express the oestrogenreceptor in the SF9 insect cells (ATCC CRL1711), according to the knownmethodology mentioned previously.

2*10⁷ SF9 cells are cultured in a 175 cm² "Falcon" flask in the TNM-FH"SIGMA" medium supplemented by 10% of foetal calf serum (FCS) and by 50microgram/ml of gentamycin. After infection then incubation at 27° C.for 40 to 42 hours, the cells are lysed in 1 ml of lysis buffer (Tris 20mM-HCl pH8, EDTA 0.5 mM, DTT 2 mM, Glycerol 20%, KCl 400 mM) with afreezing-thawing cycle which is repeated another two times. Thesupernatant, containing the recombinant human oestrogen receptor is keptin liquid nitrogen by 0.5 ml doses.

The supernatant is incubated at 0° C. for 24 hours with a constantconcentration (T) of tritiated oestradiol in the presence of increasingconcentrations of either unlabelled oestradiol (0-000×10⁻⁹ M), or ofunlabelled product to be tested (0-25000×10⁻⁹ M). The concentration ofbound tritiated oestradiol (B) is then measured in each incubate by thetechnique of adsorption with carbon dextran.

Calculation of the Relative Bond Affinity (RBA):

The following two curves are drawn: the percentage of bound tritiatedhormone 100×B/B0 as a function of the logarithm of the concentration ofunlabelled reference hormone or as a function of the concentration ofunlabelled test product.

The straight line of the equation I₅₀ =(B0/B0+B min)/2=100(1+Bmin/B0)=50 (1+Bmin/B0) is determined.

B0=concentration of bound tritiated hormone in the absence of anyunlabelled product.

B=concentration of bound tritiated hormone in the presence of aconcentration X of unlabelled product.

B min=concentration of bound tritiated hormone for an incubation of thistritiated hormone at a concentration (T) in the presence of a largeexcess of unlabelled reference hormone (1000×10⁻⁹ M) for the humanreceptor.

The intersections of the straight line I50 and the curves allow theevaluation of the concentrations of unlabelled reference hormone (CH)and of the unlabelled test product (CX) which inhibit by 50% the bindingof the tritiated hormone on the receptor.

The relative bond affinity (RBA) of the test product is calculated bythe equation: RBA=100 (CH)/(CX).

The results obtained are as follows:

    ______________________________________                                                    HOR oestradiol = 100                                              Examples    24 hours                                                          ______________________________________                                        1           28                                                                2           49                                                                3            5                                                                ______________________________________                                    

Conclusion:

While these products have an affinity which is 2 to 20 times weaker thanthat of oestradiol, the fixation on the oestrogen receptor is a new factfor this family of products.

What is claimed is:
 1. A compound of the formula ##STR14## wherein X is##STR15## R₁ and R₂ are individually hydrogen or alkyl of 1 to 4 carbonatoms, R₃ is selected from the group consisting of hydrogen, halogen andalkyl and alkoxy of 1 to 4 carbon atoms, R₄ is in the meta or paraposition and is selected from the group consisting of hydrogen, halogen,--OH, alkyl and alkenyl and alkynyl of up to 4 carbon atoms, alkoxy andalkylthio of 1 to 4 carbon atoms, optionally ##STR16## R_(A) and R_(B)are individually hydrogen or alkyl of 1 to 4 carbon atoms, or takentogether with the nitrogen form a saturated 5 to 6 member ringheterocycle with an optional second heterocycle selected from the groupconsisting of oxygen, nitrogen and sulfur, n is an integer from 2 to 7,R₅ is hydrogen or halogen, R₆ and R₇ are individually selected from thegroup consisting of hydrogen, halogen, alkyl of 1 to 4 carbon atoms andphenyl optionally substituted in the meta or para position with R₄ andtheir addition salts with non-toxic, pharmaceutically acceptable basesand acids, with the provisos that X is not (A), when R₁, R₂, and R₃ arehydrogen and R₄ is --OH and X is not (B) when R₅ and R₆ and R₇ arehydrogen or when R₅ and R₆ are hydrogen and R₇ is alkyl of 1 to 4 carbonatoms.
 2. A compound of claim 1 wherein X is ##STR17##
 3. A compound ofclaim 1 wherein X is
 4. A compound of claim 1 having the formula whereinR'₁, R'₂ and R'₃ are individually hydrogen or alkyl of 1 to 4 carbonatoms and R'₄ is in the meta or para position and is selected from thegroup consisting of hydrogen, halogen, --OH, alkyl of 1 to 4 carbonatoms, ##STR18## and and n, R_(A) and R_(B) are defined as in claim 1.5. A compound of claim 4 wherein R'₁, R'₂ and R'₃ are hydrogen.
 6. Acompound of claim 1 wherein R₆ is halogen or ##STR19## and R₇ ishydrogen.
 7. A compound for treating disorders linked tohypofolliculinia comprising an amount of a compound of claim 1sufficient to treat hypofolliculinia and an inert pharmaceuticalcarrier.
 8. A compound of claim 1 selected from the group consistingof:5-[4-[2-(dimethylamino) ethoxy] phenyl] 6-(4-hydroxyphenyl)2-naphthalenol, 1,5-dichloro-6-(4-hydroxyphenyl)-2-naphthalenol,5-chloro-6-(4-hydroxyphenyl)-2-naphthalenol.
 9. A preparation processfor the products of formula (I) as defined in claim 1, characterized inthat a product of formula (II):

    G--[X]--OP'                                                (II)

in which [X] is as defined in claim 1, P' represents a protective group,and G represents a halogen atom or an OSO₂ CF₃ group is subjected to theaction, in the presence of a catalyst, of a product of formula (III):##STR20## in which Y represents a halogen atom, a B(OH)₂ group or anSn(R)₃ group, in which R represents an alkyl group containing from 1 to8 carbon atoms and P represents a protective group, in order to obtain aproduct of formula (IV): ##STR21## in which P, P' and have the samemeaning as previously, which product of formula (IV) is subjected to oneor more deprotection reactions in order to obtain the expected productof formula (I) which, if appropriate, is subjected to the action of anacid or base in order to obtain the corresponding salt.
 10. Apreparation process for the products of formula (I) as defined in claim2, characterized in that a product of formula (V): ##STR22## in which R₄is as defined in claim 1, and in which P is a protective group issubjected to the action of the methylvinylketone of general formula(VI): ##STR23## in which R₁, R₂ and R₃ are as defined in claim 1, inorder to obtain the product of formula (VII): ##STR24## in which R₁, R₂,R₃, R₄ and P are as defined previously, which is subjected to the actionof a dehydration and aromatization reagent in order to obtain theproduct of formula (VIII): ##STR25## in which R₁, R₂, R₃, R₄ and P areas in claim 1, which is subjected to the action of a deprotectionreagent in order to obtain the products of formula (I) which, ifdesired, is subjected to the action of an acid or base in order toobtain the corresponding salt.
 11. A method of treating hypofolliculiniadisorders in warm-blooded animals by administering in warm-bloodedanimals in need thereof an hypofolliculinially effective amount of atleast one compound of claim 1.